Abstract Features shared by all neurodegenerative diseases represent critical research targets. All follow a characteristic, anatomical sequence, with lesions that spread along functional neuronal network pathways. Despite these commonalities, each disease features a distinct anatomical pattern of early regional vulnerability. These disease-specific anatomical patterns guide translational research by focusing attention on the most relevant targets in humans and model organisms and emphasize the need to identify which brain areas degenerate first in each disease. Strong evidences suggest that specific brainstem (BS) nuclei develop neurofibrillary changes before the cortex in AD. In FTLD, early reports suggest BS neurodegeneration, but few studies have addressed this issue using TDP-43. This information may prove relevant for deciphering early regional vulnerability, anatomical progression and possible non- cognitive symptomatology. Our long-term goal is to provide an integrated picture of BS vulnerability in AD and FTLD-TDP and to incorporate this understanding into the etiopathogenesis of these diseases. The overall objective of this application is to identify the BS histopathological and cytoarchitectonic changes in AD and FTLD-TDP by using a comprehensive network-based approach in well characterized human brains. We will study how often and early these nuclei are involved, whether the changes are symmetric and have a topographical gradient, and which clinical manifestations are associated. This proposal is based on the hypothesis that selected BS nuclei are interdependently and constantly involved in very early stages of AD and FTLD-TDP. Clarifying BS involvement in these diseases will facilitate development of biomarkers, improve diagnostic clinical criteria, and suggest therapeutic targets. The hypothesis will be tested by pursuing two specific aims: To determine the chronology, severity, interdependence, and symptom-relevance of neuropathological changes in the isodendritic core in AD vs. healthy elderly controls and in FTLD vs. healthy elderly controls. This approach is innovative because it utilizes brains processed into thick histological slides and 3D reconstructed. This method is superior in quality, quicker and more economical than the traditional methods and renders excellent stereological and immunohistochemical studies. In addition, the control groups will be composed of a large number of difficult-to-get healthy elderly. This proposal is significant because it is expected to that the knowledge gained will highlight unrecognized early symptoms and suggest new biomarkers and potential therapies. Integrative histopathological and cytoarchitectonic studies remain critical to understanding AD and FTLD and will serve as a foundation for ongoing and future translational research.